The incidence of gestational diabetes mellitus, which is 2% to 5%1–4 in singleton pregnancies, is increased in multiple gestations.5 Several factors may contribute to this increased rate of gestational diabetes in women with multiple gestations, including advanced maternal age; infertility due to polycystic ovary syndrome and its associated insulin resistance state6; and greater placental mass and, therefore, increased levels of diabetogenic hormones (eg, human placental lactogen, cortisol, and progesterone). These diabetogenic hormones have been shown to affect β‐cell function and sensitivity to insulin.7,8 The rate of multifetal pregnancies has increased dramatically in the past decade, largely because of the use of ovulation induction and assisted reproductive technologies.9,10 The adverse effects of gestational diabetes may complicate the already high risks of multifetal pregnancies.
Fetal reduction is offered to all women with triplet pregnancies at the Sheba Medical Center. This allowed us to assess whether a change in the size of the fetal–placental unit influences the occurrence of gestational diabetes. We compared the rate of gestational diabetes among women with triplet pregnancies with that among women who underwent fetal reduction to twins, while controlling for other factors that may influence the rate of gestational diabetes.
MATERIALS AND METHODS
Women who conceived triplet pregnancies at our institution between 1994 and 1998 were eligible for inclusion. Exclusion criteria were overt diabetes, quadruplet or higher order pregnancy, reduction of more than one fetus, and delivery before 25 completed weeks of gestation. Retrospective analysis was done on 188 consecutive triplet pregnancies that were eligible. One hundred three pregnancies continued as triplets, and 85 women elected to undergo fetal reduction to twins. Fetal reductions were performed by one physician using transab‐dominal ultrasonography–guided intrathoracic potassium chloride injection at 10 to 14 weeks of gestation.
The main outcome variable measured was the incidence of gestational diabetes. All women were screened for carbohydrate intolerance by performing a 1‐hour glucose challenge test between the 24th and 28th week of gestation. If the plasma glucose level was greater than 130 mg/dL, a 3‐hour, 100‐g oral glucose tolerance test was performed. Women who received steroids for pre‐term labor were screened at least 5 days after therapy. Gestational diabetes, defined as glucose intolerance with onset or first recognition during pregnancy, was diagnosed by using the criteria of Carpenter and Coustan.11 Only patients with two abnormal values were considered to have gestational diabetes. Women in whom gestational diabetes was diagnosed were followed in a specialized diabetes‐in‐pregnancy program. All women were seen by a registered dietitian for individual consultation and were placed on an 1800‐ to 2200‐calorie American Diabetes Association diet. All women were given a memory‐based blood glucose meter and were instructed to measure capillary blood glucose while fasting and 2 hours after meals. Insulin therapy was begun when capillary blood levels exceeded 95 mg/dL in the fasting state or 120 mg/dL in the postprandial state.
Information was collected on risk factors for gestational diabetes, including advanced maternal age; family history of diabetes, parity, and prepregnancy body mass index (BMI). Data were collected from hospital records and personal interviews. Statistical analysis was performed by using χ2 and Student t‐tests as appropriate. A P value < .05 was considered significant.
Demographic characteristics did not differ between the two groups (Table 1). Table 2 shows the risk factors for gestational diabetes for both groups. One woman in each group had a history of gestational diabetes; however, neither women went on to develop gestational diabetes in the target pregnancy. No difference in parity and prepregnancy BMI was found between the groups. Women in the triplet group were more likely to have a positive family history for diabetes and a higher BMI at the end of pregnancy, as expected. Table 3 shows maternal and neonatal outcomes. The rate of gestational diabetes was significantly higher in the triplet group than in the reduction group (22.3% vs 5.8%, P = .003). The rate of preeclampsia did not differ between the groups (13.5% vs 10.6%).
Gestational age at delivery was significantly lower in the triplet group than in the reduction group (33.4 ± 2.8 weeks vs 36.0 ± 2.8 weeks, P < .001). The rate of cesarean delivery was significantly higher in the triplet group than the reduced group (89% vs 59%, P < .001). Mean birth weight per pregnancy was significantly lower in the triplet group than the reduction group (1764 ± 448 g vs 2208 ± 526 g, P < .001).
When the triplet group was stratified, the birth weight of triplets of diabetic women did not significantly differ from that of triplets of nondiabetic women (1829.4 ± 489.4 g vs 1746.9 ± 491.2 g, P = .21). Gestational age at delivery was also similar between the two groups (33.8 ± 2.9 weeks vs 33.3 ± 2.8 weeks, P = .47).
Our findings suggest that placental mass and number of fetuses contribute significantly to the occurrence of gestational diabetes. Previous studies have provided conflicting evidence on the rate of gestational diabetes in triplet compared with twin pregnancies (Table 4). Seoud et al5 reported a higher rate of gestational diabetes in triplet pregnancies than in twin pregnancies (38.5% vs 3.1%). In contrast, Smith‐Levitin et al13 reported no significant difference in the rates of gestational diabetes (7% and 5%, respectively) in women with twins after reduction and those bearing nonreduced triplets. In a retrospective review of 57 triplet pregnancies, Albrecht et al14 found a gestational diabetes rate of 10.5%, whereas Malone et al15 found a 7% rate of gestational diabetes in such pregnancies. One explanations for these inconsistencies is that the factors influencing the rate of gestational diabetes were not well controlled (eg, maternal age, parity, family history of diabetes, infertility, and BMI).
Gestational diabetes mellitus is characterized by abnormalities in both insulin sensitivity and insulin secretion.7,15–18 However, the degree to which each of these abnormalities contributes to the pathogenesis of gestational diabetes is not clearly established. The fact that fetal reduction decreases the risk for gestational diabetes by more than threefold suggests that under extreme circumstances, when placental mass is large and levels of diabetogenic hormones are substantially increased (as is the case in multifetal pregnancies), insulin resistance may be primarily responsible for the development of gestational diabetes.
A study19 that used methods similar to ours to study the rate of hypertensive disorders in triplet pregnancy found that the rate of hypertension decreased threefold after fetal reduction. Our data did not confirm this finding. However, other groups (Table 4) have also reported an increase in preeclampsia in triplet pregnancies.5,13 Of note, several investigators have suggested that insulin resistance may contribute to the occurrence of both preeclampsia and gestational diabetes.20–22 Therefore, insulin resistance, which probably increases in triplet pregnancies because of the increased production of diabetogenic hormones by the placenta, may represent a common link between these disorders.
It is in theory possible that gestational diabetes is a physiologic adaptation rather than a pathologic condition in multifetal pregnancies. One could speculate that the hyperglycemic state provides for the increased demand for nutrients in this condition. However, in our study, the newborns of diabetic mothers with triplet pregnancy were not significantly larger than those of their nondiabetic counterparts. Additional studies are needed to examine whether the diagnostic criteria for gestational diabetes should be altered in multiple gestations.
The dramatic increase in gestational diabetes in our sample has potential implications for counseling women with multifetal pregnancies. Although the risk for gestational diabetes would probably not be a determining factor in a couple's decision to perform reduction, gestational diabetes also increases the risk for neonatal complications. Diabetes has been associated with such conditions as the respiratory distress syndrome, macrosomia, and neonatal hypoglycemia; their rates of occurrence in triplet pregnancies is not known. Accelerated growth, associated with hyperglycemia, might actually be beneficial in triplet pregnancies, which are known to be at risk for low birth weight. In contrast, the increased risk for the respiratory distress syndrome among infants of diabetic mothers is a concern in view of the increased risk for preterm birth in multifetal pregnancies. From the maternal point of view, the need for a special diet, frequent blood testing and perhaps insulin therapy would make an already difficult pregnancy more demanding. Studies are needed to address these issues.
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